Summary/Abstract Calcium, a versatile signaling molecule, is a critical mediator of many cellular processes, including muscle contraction, transcription, cell division, and synaptic vesicle release. Paradoxically, calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium signaling can affect cells in different ways and to varying degrees. Consequently, calcium levels need to be tightly controlled. Indeed, defective calcium signaling has been implicated in many neurodegenerative diseases, muscular dystrophies and heart disease. To understand the regulation of calcium signaling, we are exploiting the model system Caenorhabditis elegans to identify critical components that are involved in the regulation of calcium handling. From our non-biased genetic studies, we have found a novel role for a conserved protein, SEL-12, in endoplasmic reticulum calcium handling which is critical for mitochondria morphological organization and function. SEL-12 is the C. elegans homolog of presenilin. Mutations in presenilins are the most common cause of early onset familial Alzheimer's disease. Despite the identification of the involvement of presenilin in Alzheimer's disease over 20 years ago, the functional consequences of mutations in presenilin are not understood. Here, we propose to examine the function of SEL-12 in C. elegans to understand its role in calcium handling and mitochondrial activity and gain insight into Alzheimer's disease pathology. Thus, using the strengths of the C. elegans, we are taking a multifaceted approach utilizing live cell imaging in concert with genetic, molecular and cell biology techniques to test the following hypothesis: Presenilin/SEL-12 functions to regulate endoplasmic reticulum calcium signaling and that in the absence of presenilin/SEL-12 function calcium transfer to the mitochondria is increased impacting mitochondrial function and cellular fitness. We believe our studies will provide novel understanding into the mechanisms that arise in Alzheimer's disease and will, therefore, provide unique insight into the development of new therapeutic strategies for Alzheimer's disease.